Process for the manufacture of pentaenes



Patented Feb. 6, 1951 PROCESS FOR THE MANUFACTURE OF PENTAENES Otto Isler, Basel, Switzerland, assignor to Hoffmann-La Roche Inc., Nutley, N. 3., a corporation of New Jersey No Drawing. Application June 7, 1947, Serial No. 753,383

12 Claims. 1 This invention relates to the manufacture of pentaenes.

Various syntheses for the preparation of vitamin A ethers have been described. According to the .known methods, the carbon skeleton of vitamin A consisting of 20 carbon atoms is built up as follows: 6-(2',6',6'-trimethyl-cyclohexene- (1)-y1-4-methylhexadiene-(3,5) yne (1) and 6 (21616 -trimethyl-cyolohexene (1) -yl)-3hydroxy-4-methyl-hexene- (4) -yne- (1) are condensed with ethers of 1-hydroxy-butanone-(3) (C s+C4=C20; of. U. S. A. Specifications Nos. 2,369,157 and 2,382,086). Alternatively, 4-

(2,6',6 -trimethy1-'cyclohexene (1') yl) 2- methylbutene-(2)-al-(1) is reacted with 1- methoxy-3-methyl-pentene-(2)-yne-(4) or with ethers of 1,3-dihydroxy-3-methyl-pentyne-(4), C14+Cs=Czu, cf. Experientia, vol. 2, year 1946, page 31; U. S. A. Specification No. 2,369,157; Festschrift Emil Barell, Basel, year 1946, page 31; Science, vol. 103, year 1946, page 581). Finally, it has become known in the form of preliminary communications that syntheses of the vitamin A methyl ether can be carried out as In Switzerland December 31, 1946 butene-(2) C15+C5=C2o; cf. Journal of the American Chemical Society, vol. 67, year 1945,

page 1627), or reacting 4-(2',6,6'-trimethylcyclohexene-(l) -y1) -butene-(3) one (2) (,6- ionone) with 1 methoxy 3-methy1-6-bromohexadiene-(2,4) (C13+C7=C20; of. Chemistry and Industry, vol. 58, year 1939, page 802).

The last two syntheses are not supported by any biological tests, and the ultra-violet absorption spectrum published in connection therewith shows no absorption maxima at 328 mu as would be characteristic for vitamin A ethers (of. Journal of the American Chemical Society, vol. 67, year 1945, page 1627).

It has now been found, according to the present invention, that vitamin A ethers can be obtained by condensing p-ionone with an ether of 1-hydroxy-3-methyl-6-halogeno-hexene- (2) yne-(4) by means of zinc, cadmium or magnesium, but preferably zinc, and, in optional sequence, partially hydrogenating and dehydrating the ether of 1-hydroXy-3,7-dimethyl-7-hydroxy 9 trimethyl cyclohexenyl nonadienefollows. Reacting 5-(2',6',6'-trimethy1-cyc1o--' yne-(4) thus formed. hexene- (1')-yl) 3-hydroxy-3-methy1-pentene- The synthesis is illustrated by the following (4)-yne-(1) with 1-methoxy-3-methyl-4-chloroformulae:

CH3 OH! H F CH=CH-CO Ha1-CH:-CECO=CH-GHOR JJ s 011, l

I II CE: CH: OH

oH=oH('1oH20Eoo=oHcH2oR I H3 H3 III CH3 CH; 0113 011a CH: C

H3 H3 CH3 3 According to the present invention, the synthesis of vitamin A ethers may be carried out as follows: Reacting fi-ionone (I) containing 13 car bon atoms in the molecule with an ether of va "with B-ionone were not hitherto known. They 'may be prepared in the following mannerfrom 3 hydroxy 3 methyl-pentene-(l) -yne-('4), or from the ethers of l hydroxy-3-methyl-pentene- (2) yne- (4) 3-hydroxy-3-methyl-pentene- (1) yne-(4) is halogenated with phosphorus tribromide, and the primary bromide thus formed is etherified with an alkali metal alcoholate. 1- methoxy-3-methyl-pentene- (2) -yne- (4) is-known (see, for example, Festschrift Emil Barell, year 1946, page 40) The 1-butoxy-3emethyl-pentene- (2) -yne-(4) boils at 71C. to"74 C. under a pressure of mm. Hg; n =1.45(J. 1-nhenoxy-3- methy1-pentene-(2) -yne-(4') boils at 75 C. to 78 C. under a pressure'Of'0.05 mm. Hg; :1518. The ethers of 1Phydroxye3-methylepentene- 2) yne-(4) are condensed with formaldehyde by methods known per se. From 1,-metnoxy-3- methyl-.pentene-(2)-yne-(4) and 33 per cent. aqueous formaldehyde, ina manner analogous to the method described in Swiss Specification No. 223,202, 1-methoxy-3-methyl-6-hydroxy hexene- (2) -yne(4) can be obtained in a 70 per cent. yield in the presence of copper catalysts in a sealed vessel at 120 C. Its boiling point is 127-129 C. under a pressure of 15 mm. :Hg;

n =1.496. The ethers of 1-hydroxy-3-methyl- G-hydroxy-hexene- 2) -yne- (4) are transformed, preferably immediatel before condensation with zinc, cadmium or magnesium is performed, in ethereal solution and by the action of a phosphorus trihalogenide in the presence of a small m proportion of pyridine, into the ethers of l-hydroxy-3-metnyl-6halogeno-hexene- (2) -yne- (4) They are liquids of very low viscosity which irritate the mucous membrane. l-methoxy-3- methyl-6bromo-hexene-(2)-yne(4) is an oil,

clear as water, n =1.524.

The first step of the process of the present invention is a condensation by means of zinc, cadmium or magnesium, by which ethers of l-hydroxy 3 methyl 6 halogeno --'-hexene (2) yne-(4) and B-ionone are combined-(with each other, "similar'to a-Pteformatski synthesis. The reaction may be carriedout in an inert solvent, dry ethyl ether being especially'suitable. Preferably, excess halide is employed, and the solution of the reaction components is allowed to flow into the warmed condensing agent,.e. g. zinc powder, while stirring vigorously. The zinc, cadmium or magnesium compound of the condensation prodnot formed is hydrolysed'iin-rthe usualImanner,

for example by means of l per scent. sulphuric acid. Non-reacted fi-ionone may be separated oil" in the form of a crystallising derivative, for example, as its semi-carbazone. The ethers of 1 hydroxy-3,7-dimethyl-7-hydroxy 9 trimethylcyclohexenyl-nonadiene (2,8) yne-(4) formed may be purified by partition betweenisolvents, such as low boiling petroleum ether and aqueous methyl alcohol, or by careful distillation in high vacuum.

The purifiedcon'densation products are viscous, yellow oils, not absorbing any ultra-violet rays -of.higher wave length than 260 ma. Determination according to .Zerewitinofi yields values for 1 active =hydrogen-atom, and, on heating, the condensation products split off water easily.

Thereupon, condensation product III is subjected, preferably after purification, to partial hydrogenation of the triple bond. Means usually employed for polyene compounds may be applied, such as, for example, treatment with zinc and acetic acid, Withsodium amalgam and a basic agent, or'with sodium inli'quid ammonia. Catalytic hydrogenation by means of "palladium charcoaluntowh'ich' quinoline hasbeen adsorbed prior to use, orpalladium-calc'ium carbonate'or palladium-barium sulphateascatalyst has'proved to be'especially suitable. In catalytic partialhy drogenation, the introduction of hydrogen is 'discontinued after the-calculated quantity of hydrogen has been taken up. His not necessaryto isolate and to purify the hydrogenation product, i. e., the-ether of l-hydroxy 3fl dimethyl-mhy- 'droxy 9 -trimethyl cyclohexenylnonatriene- (2,4,8). Itis a viscous, yellowish-oil.

In order to introduce a'further' double 'bond, product IV of the partial hydrogenation, i. e., the ether of 1-hydroxy-3,-7-dimethyl-'7- hydroxy '9 -trimethyl cyclohexenyl nonatriene (2,418)

is subjected to dehydration. The usual' methods may be employed (c'f. Houben-Weyl, Methoden der organischen Chemie, "3rdedition, =vol. pages 947 952), provided the desired pentaene remains stable and nofissionp'f the:carbon-'ch'ain of compoundIV occurs. For de'hydraLtionmurposes, agents splittingwfi water, such as oxalic acid, phenyl 'isocyanate, aluminum hydroxide,

:magnesium methyl bromide, 'may be employed.

'It is of advantage tozboiliin ant iner'tvsulvcnt :of boiling point above 100 C., such as toluene. The further double 'bond may also be introduced by esterifying compound IV with an organic acylating agent and splitting off acid from the ester formed by heating, preferably in the presence of an alkaline medium. Furthermore, dehydration can also be arrived at by replacing, under careful-conditions, the hydroxy group by halogen whereupon ihydrogen halide is slit off by means of alkaline medium. Thus, for example, reaction with phosphorus trichloride in the presence of pyridine and .subsequent heating with methyl alcoholic alkali hydroxide at C. to C. has proved suitable.

Pentaenes (vitamin A ethers) can also be obtained by the following process with interchanged reaction sequence. Condensation product III ether of 1 hydroxy-3l7 dimethyl-7-hydroxy-9- trimethyl cyclohexenyl nonadiene (2,8)-

yne-(4) is first subjected ito .dehydration, and the compound thus formed "is partially hydrogenated at the triple bond by the action of '1 mol .of hydrogen. This process is illustrated by Formulae .-I, II, III, VI and V in the above formulae. The measures to be taken for each step-are the same as described above. It is possible to combine several steps.

For the preparation of vitamin A methyl ether, p-ionone and l-methoxy-3-methyl-fi bromo-hex- .ene-(2)-yne-(4) are condensed in an ethereal solution by means of zinc, cadmium or mag is left to stand for 12 hours.

nesium. The 1-methoxy-3,7-dimethyl-7-hydroxy 9 trimethyl cyclohexenyl nonadiene- (2,8) -yne(4) thus formed is hydrogenated with 1 mol of hydrogen at the triple bond by the action of hydrogen in the presence of palladiumcalcium carbonate as catalyst. The 1-methoxy- 3,7 dimethyl '7 hydroxy 9 trimethyl-cyclohexenyl-nonatriene-(2,4,8) obtained is treated with agents capable of splitting off Water, preferably in the presence of a solvent. Alternatively, the process may be carried out as followsi F01 dehydrating purposes, the 1-methoxy-3,'7-dimethyl 7 hydroxy 9 trimethyl cyclohexenyl-nonatriene-(2,4,8) may be reacted with 1 mol of phosphorus trichloride in the presence of pyridine, whereupon the 1-methoxy-3,7-dimethyl 7 chloro 9 trimethyl cyclohexenylnonatriene-(2,4,8) obtained is heated with alkali hydroxide in methyl alcohol or pyridine.

The products obtained in accordance with the present process, i. e., vitamin A'ethers, may be purified by the same methods as are known for high concentrates of vitamin A and its derivatives obtained from natural sources (i. e. partition between solvents, chromatographic adsorption, careful distillation and the like). As required for vitamin A preparations from natural sources, the products of the present process must be protected against the destructive influence of light, air and heat. It is advisable to add anti- 1 oxidants which may also be present during the various steps of the synthesis; tocopherols have proved to be especially suitable as anti-oxidants.

Example 1 A solution of 5.6 parts by weight of 1-methoxy- 3-methyl-6-bromo-hexene-(2) -yne-(4) and 3 parts by weight of B-ionone in parts by volume of ether are allowed to flow in a nitrogen atmosphere into 4 parts by weight of warmed zinc powder in the course of half an hour while stirring vigorously, the reaction heat being suflicient to keep the solvent boiling under a reflux condenser. When the'intensity of the reaction decreases, the mixture is heated for a short time, cooled down and decomposed with ice and dilute sulphuric acid. Thereupon it is taken up in ether, successively washed with l'per cent. sulphuric acid and water, dried, and the solvent is evaporated. The residue is dissolved in methyl alcohol, semi-carbazide is added, and the mixture The mixture is filtered, double the quantity of water is added, then it is taken up in petroleum ether of boiling range -70 C., and the petroleum ether solution is shaken out several times with 90 per cent. methyl alcohol. From the methanol extract 3 to 3.5 parts by weight of 1-methoxy-3,'7-dimethyl 7 hydroxy 9 trimethyl cyclohexenyl-nonadiene- (2,8) -yne- (4) are obtained in the form of a viscous, yellowish oil. n =1.515. The yield, calculated for B-ionone, amounts to 65-70 per cent.

10 parts by weight of this condensation product are dissolved in 100 parts by volume of methyl alcohol and hydrogenated at room temperature by means of 0.5 part by weight of 4 per cent. of palladium-calcium carbonate catalyst. After 1 mol of hydrogen has been taken up, the hydrogenation is interrupted and the catalyst separated off. In order to remove by-products (formed by premature dehydration), 6 parts of water are added to the filtrate and the mixture is shaken out with a small quantity of petroleum ether of boiling range 30-60 C. The methyl alcohol solution is then diluted with 200 parts of water, shaken out with petroleum ether, and the pound clearly promotes their growth.

A solution of 0.? part by weight of phosphorus tribromide in 30 parts by volume of petroleum ether of boiling range 30-60" C. is added in the course of one hour to a mixture of 4 parts by weight of the product obtained by the partial hydrogenation in parts by volume of petroleum ether of boiling range 30-60 C. in the prese'ncc of 1 part by volume of pyridine. After the whole quantity has been added, stirring at 0 C. is continued for 1 hour, the reaction solution is decanted from a small portion of a brown precipitate, ice is added and the mixture is washed with water, dried with sodium sulphate, and the solvent is evaporated. The residue is dissolved in 40 parts by volume of pyridine and heated to -70" C. for one hour with 2 parts by weight of pulverized potassium hydroxide while stirring. After cooling down, petroleum ether of boiling range 30-60" C. is added, washed with 90 per cent. methyl alcohol and water, dried with sodium sulphate, and the solvent is evaporated, finally by means of vacuum.

Purification of the vitamin A methyl ether may be carried out by means of a percolation chromatogram through columns of weakly active aluminum oxide, by means of petroleum ether of boiling range 60-80 C. Thereby intermediates with one free hydroxyl group adhere to the aluminum oxide, whereas by-products, absorbing ultra-violet light at 280-310 me, are less well adsorbed and concentrate in the first runnings. The vitamin A methyl ether slowly moves through the column; during this process its position can easily be detected by means of its intensive yellow-green fluorescence in the ultraviolet light. The desired fraction is characterised by the stability of the Carr-Price colour reaction. lhe petroleum ether is evaporated and the purified vitamin A methyl ether thus obtained is distilled in a molecular still. i is a yellow oil of boiling point 90-95" C. under a pressure of 10* mm. Hg with its characteristic absorption maxima at 328 m It is of high biological activity.

Example 2 4 parts by weight of l-methoxy-3,7-dimethyl- 7 hydroxy 9 trimethyl cyclohexenyl nonatriene-(2,4,8) (prepared in accordance with EX- ample 1) are dissolved in 40 parts by volume of acetic anhydride, whereupon 4 parts by weight of anhydrous sodium acetate are added and the mixture is refluxed for 2 hours. Excess acetic anhydride and the glacial acetic acid formed are then evaporated in vacuo and the residue is taken up in petroleum ether of boiling range 30-60 C. and water. The petroleum ether solution is successively washed with sodium bicarbonate solution and water, dried with sodium sulphate and concentrated. A yellow oil of boiling point C. under a pressure of 10* mm. Hg is obtained. In the. ultra-violet spectrum it shows absorption within the range characteristic for .7 "pentaenes (315-.-,335.m whentestedon vitamin A deficient rats it proves to be highlyiactive.

- iI heproductncanlbe purified according to the methods described in.-Example 1.

Example 3 parts by weight of 1-methoxy-3,7-dimethyl- '7 hydroxy 9 trimethyl cyclohexenyl nonatriene-(2,4,8), prepared in accordance with EX- ample 1, are dissolved in 100 parts by volume of dioxane, 2.5 parts by weightof anhydrous oxalic acid are added, and the mixture is stirred for one hour at C. After cooling down, the product .is taken up in petroleum ether of boiling range 30-60 C., successivelywashed with '95 per cent. methyl alcohol and'water, dried and the .solvent is evaporated.

Example 4 2 parts by weight of l-methoxy-3,7-dimethyl- '7 hydroxy 9 trimethyl cyclohexenyl nonadiene-(2,8) -yne-(4), prepared in accordance with Example 1, are refluxed for onehour with 5 parts by weight of pulverised zinc in "6 parts by volume of 80 per cent, acetic acid. 'Thus,'partial hydrogenation of the triplebond and dehydration can be carried out in one single reaction step. After cooling down, the reaction'product is taken up in petroleum ether' of boiling range 3"0-60 C. and worked up as described inExample 1.

I claim:

1. Process for the manufacture of penta enes, comprising condensing toy-means of a metal selected from the group consisting of.zinc, 'magnesium and cadmium, fl-ionone-zwith'an ether of 1 hydroxy 3 methyl 6 -'ha1ogeno hexene (2) yric-(4) to produce a corresponding ether of 1 hydroxy 3,7 dimethyl 7 hydroxy 9 -'trimethyl cyclohexenyl nonadiene- (2,8) -'yne (4) and treating said'latter diene-yne by aprocess which successively comprises the steps of hydrogenating and dehydrating.

2. Process according to claim 1, comprising "efiecting the dehydration by esterifying with an organic acylating agent and subsequently splitting ofi 'acid by heating under alkaline conditions.

3. Process in accordance With claim F1, icomprising e'fiecting the dehydration'by reactingwith 'a phosphorus-halide and splitting 'oif'hydrogen halide from the halogeno compound formed by reacting with an alkaline compound.

4. Process for the manufacture of pentaenes, comprising condensing, bymeans of zinc, fi-ionone with a low alkyl ether ".Of l-hydrox -3- methyl-fi-halogenoehexene- (2) eyne- (4-) hydrogenating the low alkyl ether of l--'hydroxy 3,7-

8 dimethylv'7 hydroxy 9 trimethyl cyclohexenyl-nonadiene-'(2;8) -yne- (4) and subjecting to dehydration the low alkyl ether of .l-hydroxy- 3L7 dimethyl 7 'hydroxy 9 trimethyl cyclo-hexenyl-nonatriene-(2,4;8) formed.

'5. Process "forthe manufacture "of pentaenes, comprising condensing by means of zinc, 13 lo- .none' with 1 rmethoxy-ii -methyl-6 bromo -hexene- (2)-yne-(4), partially hydrogenating at the triple bond, the 1-"methoxy 3;7-dimethyl 7 hydroxy 9 'trimethyl cyclohexenyl nonadiene-(2,8)-yne-(4) and dehydrating the l-me- 'thoxy 3,7 dimethyl '7 hydroxy '9 tri- Number none with an ether of l-hydroxy-3-methyk6- 'ha'logeno hexene- (2) -yne- (4') inthe presence of a m'emberselected .from the -L group (consisting of zinc, magnesium and cadmium.

10. Process which comprises condensing 1?- ionone with l-lower -';alkoxy'-3-methyl-G-halogeno-hexene-(Zi-yne-M) fin =the presence of a member selected 'from the group consisting of zinc, magnesium and cadmium.

"llfiProcess which comprises condensing 3- ionone with l-methoXy-3emethyl-6-halogenohexene-(2) -yne-(4=) in'the presence of a member selected from the group .consisting of zinc, magnesium and cadmium.

'12..Process which comprises condensing B- 'ionone with 1-methoxy-3-methyl 6-bromo-hexene- (2) -yne- (4) in the :presenceof'zinc.

:OTTO ISLER.

"REFERENCES CITED 'The following references are of #record'in the file ofthis patent:

UNITED .STATES PATENTS Name Date iMil'as Dec. 10, 1946 OTHER REFERENCES Kipping et al.: Chemistry and Industry, vol.

.58 (1939) page 802.

-Oroshnik: Jour. Amer. Chem. Soc, vol. .67

(1945), pa es 1627, 1628. 

1. PROCESS FOR THE MANUFACTURE OF PENTAENES, COMPRISING CONDENSING BY MEANS OF A METAL SELECTED FROM THE GROUP CONSISTING OF ZINC, MAGNESIUM AND CADMIUM, B-IONONE WITH AN ETHER OF 1-HYDROXY-3-METHYL-6-HALOGENO-HEXENE(2)-YNE-(4) TO PRODUCE A CORRESPONDING ETHER OF 1-HYDROXY-3,7-DIMETHYL-7-HYDROXY-9-TRIMETHYL-CYCLOHEXENYL-NONADIENE-(2,8) - YNE (4) AND TREATING SAID LATTER DIENE-YNE BY A PROCESS WHICH SUCCESSIVELY COMPRISES THE STEPS OF HYDROGENATING AND DEHYDRATING. 